Absorption, distribution, metabolism and excretion of [14C]ebastine after a single administration in rats

Absorption, distribution, metabolism and excretion of ebastine (4'-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone, LAS-90, CAS 90729-43-4), a novel antihistamine, were investigated with 14C-labeled compound in rats after a single oral or intravenous administration, in comparison with [14C]carebastine, an active metabolite of ebastine. After intravenous administration of [14C]ebastine at 2 mg/kg, the plasma level of radioactivity decreased biphasically with alpha-phase half-life (t1/2 alpha) of 1.6 h and beta-phase half-life (t1/2 beta) of 3.1 h. After administration of [14C]carebastine, a similar plasma level-time profile was observed with t1/2 alpha of 0.7 h and t1/2 beta of 2.1 h. Following oral administration of [14C]ebastine at a dose of 2 mg/kg, the plasma level reached the maximum (Cmax) of 102 ng eq./ml at 2 h and decreased monophasically with t1/2 of 3.9 h. At 20 mg/kg, a monophasic decrease was also observed with Cmax of 1110 ng eq./ml at 4 h and with t1/2 of 4.0 h. After oral administration of [14C]carebastine at 2 mg/kg, the plasma level reached Cmax of 129 ng eq/ml at 2 h, followed by a monophasic decrease with t1/2 of 2.9 h. Half-lives after administration of [14C]ebastine were somewhat longer than those after administration of [14C]carebastine. The level of [14C]ebastine radioactivity in the liver was about 36 times higher, and in kidney, mesenteric lymph nodes, lung, adrenal, submaxillary gland or pancreas 2-4 times higher than in plasma at 2 h after oral administration. The brain level was lower than the reliable limit of measurement. Other tissue levels were similar to or lower than plasma level. Radioactivity in most tissues decreased essentially in parallel with that in plasma. In pregnant rats, [14C]ebastine radioactivity level in fetus was about 1/4 of the maternal plasma level 1 h after administration. In lactating rats, milk levels of [14C]ebastine radioactivity were similar to maternal plasma levels over 8 h. Serum protein binding of [14C]ebastine was more than 99.8%. After intravenous administration of [14C]ebastine, about 6% of the dose was excreted in the urine and about 93% in the feces. Similar results were observed after oral administration at 0.2, 2 and 20 mg/kg. Following administration of [14C]carebastine, the recovery of radioactivity in urine and feces were around 2% and 96% of the dose, respectively, irrespective of administration route. In the plasma 2 h after oral administration of [14C] ebastine, carebastine and the polar metabolite(s) were observed as major components, whereas ebastine was hardly detected.(ABSTRACT TRUNCATED AT 400 WORDS)